1. Field of the Invention
The present invention relates to an enteric coated granule comprising a raw granule comprising a medicinal ingredient and at least two enteric coating layers different in the solubility pH; and a method for preparing the enteric coated granule.
2. Description of the Related Art
In recent years, granules have been preferred to tablets from the biopharmacological viewpoints because there is a small individual difference in a discharge rate from the stomach and an absorption property and less influence by diet. Enteric coating is selectively employed for protecting a drug which will otherwise lose its efficacy mainly by gastric acid. It has been used widely in order to prevent and protect the gastric mucosa from the stimulation of it.
It was the common practice to employ, for enteric coating, an organic solvent type coating method comprising a step of dissolving an enteric base material in an organic solvent. Instead of this method, however, an aqueous type enteric coating method comprising a step of spraying an aqueous dispersion of enteric base material powders to form an enteric film has been preferably employed in recent years. It is from the viewpoint of safety, for example, environmental safety by preventing the release of an organic solvent to the air, safety during the preparation of granules including avoidance of fire due to an organic solvent and safety and health of personnel, and safety upon administration by eliminating the residue of an organic solvent from the final dosage form. Thus, novel enteric coated granules have been developed mainly by using the aqueous dispersion type coating.
In the aqueous dispersion type coating, a dispersion of an enteric base material in water is sprayed in the mist form to coating objects such as tablets and granules. The dispersion thus sprayed adhere uniformly to the surfaces of the coating objects, but the powders of the enteric base material dispersed in the dispersion still keep their form as are and exist discontinuously on each surface. As the dispersion which has adhered onto the surfaces of the coating objects becomes dry after spraying, a plasticizer sprayed simultaneously during coating penetrates into the particles of the enteric base material and plasticizes the enteric base material, leading to the formation of a film. The necessary coating amount varies depending on the shape of the coating objects or properties of a drug or additive to be incorporated therein such as solubility in water.
With regard to the conditions of dissolution tests relating to reevaluation of medicinal drugs, dissolution tests using various test solutions have recently been required in addition to the conventional dissolution tests in accordance with the Japanese Pharmacopoeia by using a 1st fluid (pH 1.2) and a 2nd fluid (pH 6.8). The following test solutions are listed in Iyakushin No. 599.
(a) pH 1.2: 1st fluid specified in Disintegration Test of the Japanese Pharmacopoeia.
(b) pH 6.8: phosphate buffer solution (1→2) specified in Reagent and Test solutions of the Japanese Pharmacopoeia.
(c) Water: purified water specified in the Japanese Pharmacopoeia.
(d) pH 6.0: a diluted McIlvaine buffer (pH adjusted with 0.05 mol/L disodium hydrogen phosphate and 0.025 mol/L of citric acid).
Accordingly, it becomes necessary for enteric coated granules to satisfy the dissolution tests using various test solutions. This means that an enteric coated preparation has to retain acid resistance in the 1st fluid (pH 1.2) of the Japanese Pharmacopoeia and retain disintegration and dissolution properties in the 2nd fluid (pH 6.8) and moreover is required to exhibit an appropriate dissolution behavior at a pH value between these test solutions including the pH value of water. In particular, in order to retain water resistance in the dissolution test using water, the enteric coated preparation needs a large amount of coating.
An enteric coated preparation comprising a plurality of coating layers containing enteric base materials different in solubility pH is disclosed, for example, in Japanese Patent Application Unexamined Publication No. 10-203983/1998 and International Patent Application Japanese Phase Publication No. 11-506433/1999. The preparations described therein are mainly tablets having the maximum diameter of from 3 to 10 mm and are characterized in that the solubility pH of the outer enteric coating layer is higher than that of the inner enteric coating layer. An object of these preparations is to suppress the absorption of a medicinal ingredient in the small intestine and cause dissolution specifically in the colon. Accordingly, they are silent about the dissolution in water.
Enteric coated granules having at least two coating layers are described in Japanese Patent Application Unexamined Publication No. 8-109126/1996. According to the description therein, the enteric coated granules have, inside and/or outside the coating layer containing an enteric base material, a coating layer not containing an enteric base material.
In International Patent Application Japanese Phase Publication No. 2005-510539, disclosed is an enteric coated preparation comprising multiple coating layers obtained by applying protective coating on the outer surface of an enteric coating layer containing methacrylic acid-methyl methacrylate copolymer as a base material. The protective coating layer comprises a water soluble or enteric coating base material. As a specific example thereof, provided is a preparation containing two enteric coating layers wherein the inner enteric coating layer has 1:2 (molar ratio) methacrylic acid:methyl methacrylate copolymer and the outer protective coating layer has 1:1 (molar ratio) methacrylic acid:methyl methacrylate copolymer. The preparation is, however, developed not for controlling the dissolution of the granules but for physically protecting the enteric coating layer of the tablets or capsules. The 1:1 (molar ratio) methacrylic acid-methyl methacrylate copolymer contained by the protective coating layer is given as an example of a base material which is dissolved in the gastrointestinal tract earlier than the enteric coating layer so as not to disturb the drug from being released at the required site after the copolymer fulfils its purpose of protecting the enteric coating layer. Hydroxypropylmethyl cellulose acetate succinate (HPMCAS) is given as one example of the base material of such an outer layer, but its specific application is not disclosed in the publication. In addition, the above-described publication is silent about an effect on the dissolution property in water, of enteric coating layers, wherein the enteric coating layers contain HPMCASs different in the solubility pH as base materials.